Effects of FK506 on acute allograft rejection in transplanted rat heart: the role of mitogen-activated protein kinases, AP-1 and NF-kappaB

To scrutinize the effect of the immunosuppressant on acute allograft rejection as related to the intracellular signal transduction, heterotopic cardiac transplantation was performed from DA rat to Lewis rat with/without FK506. In the experimental group, recipients were given FK506 intramuscularly for 5 days. The control group received placebo. Allograft survivals were compared between two groups. For the assay of mitogen-activated protein kinase (MAPKs) families, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in the left ventricular free wall (LV) and septum (SEP) of the grafts, rats were sacrificed on POD 5 (n=5 in each group). Extracellular signal-regulated kinase (ERK) and p38MAPK were measured using Western blot analysis. AP-1 and NF-kappaB DNA binding activities were measured by electrophoretic mobility shift assay. FK506 prolonged allograft survival (6.5 vs 31 days), and suppressed activation of myocardial MAPKs (ERK: 66% in LV and 67% in SEP, p38MAPK: 62% in LV and 72% in SEP), AP-1 (24% in LV and 18% in SEP), and NF-kappaB (41% in LV and 20% in SEP) (the mean value of activities in the control group was represented as 100%). These results suggest that the signal transduction pathways may play important roles in acute allograft rejection in rat cardiac transplantation.     

Three-dimensional treatment planning using electrocardiographically gated multi-detector row CT

PURPOSE: Information concerning the amount and nature of target motion is essential for the determination of internal margin size. However, there are few published reports outlining the motion with heart and aortic pulsation. We introduce a method for three-dimensional radiation treatment planning (3D-RTP) by using electrocardiographically (ECG) gated spiral scanning with a four-section CT system. We describe a new approach to visualize internal organ motion resulting from cardiac motion with ECG gated multidetector row CT. MATERIALS AND METHODS: Five patients with lung or liver tumors were studied with a multidetector row CT system under shallow inspiration breath-holding. With retrospective ECG gating, only data acquired within a predefined interval of the cardiac cycle are used for image reconstruction. All reconstructed image data at diastolic and systolic phases of the cardiac cycle were transferred to the 3D-RTP system. The shift of the internal organs between the cardiac cycles was evaluated. RESULTS: Cardiac contraction influences anterior thorax, pulmonary peripheral vessels, and liver position, in addition to locations near the heart. Apparent movements more than 5 mm between diastolic and systolic phases were observed in the left ventricle, right atrium, and superior vena cava. Two-phase imaging was useful for showing the movement of internal organs during cardiac contraction under breath-holding. CONCLUSIONS: Spatial information using ECG-gated CT has the potential to determine the planning target volume of moving lung and liver tumors more precisely than conventional CT planning.     

Cyclooxygenase-2 expression and its relationship with proliferation of colorectal adenomas

BACKGROUND: Cyclooxygenase (COX)-2 may be linked to carcinogenesis. In the previous study, we examined COX-2 expression immunohistochemically in 95 adenomas and reported a significant correlation between its expression and the grade of dysplasia. To clarify the correlation between COX-2 expression and cell proliferation, we investigated Ki-67 labeling index using immunohistochemistry and its correlation with COX-2 expression. METHODS: Immunohistological staining for Ki-67 antigen was performed on 95 colorectal adenomas previously reported. RESULTS: The Ki-67 labeling index was significantly higher in the high-COX-2 group than in the low-COX-2 and negative groups in adenomas with moderate (44.5 +/- 6.4% vs 33.0 +/- 2.6%, 39.0 +/- 6.2%; P = 0.01, P < 0.001, respectively) or severe dysplasia (47.2 +/- 7.6% vs 40.3 +/- 7.2%, 35.0 +/- 5.4%; P = 0.02, P = 0.005, respectively). There was no correlation between Ki-67 labeling index and COX-2 expression in mild dysplasia. CONCLUSIONS: These results suggest that COX-2 may play a causal role in cell proliferation in carcinogenesis.     

Compensatory changes in static and dynamic subjective visual vertical in patients following vestibular schwanoma surgery

OBJECTIVE: Among patients with vestibular schwanoma (VS), vestibular function is nonhomogeneous, both before and after surgical removal of the VS. This paper reports investigations of neural changes, especially changes in the contribution of visual input to vestibular system integration, after VS surgery. METHODS: We examined 33 patients who underwent VS surgery via a middle fossa approach. Static and dynamic subjective visual vertical (SVV) was measured once after surgery and compared to those measured in control subjects. SVVs were assessed using a paradigm requiring the subject to manually adjust an image of a bar to the perceived vertical alignment. SVVs were measured when the background was stationary or rotating. RESULTS: In almost all patients, static SVV deviated toward the operated side. In VS subjects, the mean static SVV was 1.8+/-2.2 degrees; the amount of deviation in the dynamic SVV toward the operated side (11.7+/-8.3 degrees ) was significantly larger than that to the intact side (8.8+/-5.5 degrees ). In VS subjects, static SVV was correlated with dynamic SVV only in cases of bar adjustments toward the operated side (R=0.67, P<0.001), but not in cases of adjustments toward the intact, unoperated side. The axis of rotation was defined as the mean value of dynamic SVV for adjustments toward either side. There was only a weak correlation between the static SVV and the axis of rotation (R=0.31; P<0.05) in the control subjects. On the other hand, a more robust correlation between static SVV and axis of rotation was found (R=0.67, P<0.001) in VS subjects. There was no correlation between the static SVV and the deviation of dynamic SVV from static SVV for CCW and CW in control subjects. In contrast, there were significant correlations between static SVV and deviation of dynamic SVV from static SVV for adjustments made toward both operated (r=0.48, P<0.001) and intact sides (r=038, P<0.05). CONCLUSION: It is assumed that the amount of deviation in static SVV reflects the individual level of compensation. In addition, increased visual dependency evoked a symmetrical bias of the dynamic SVV from the measures at initial SVV assessment (i.e. static SVV or the center of tilt). As a result, we conclude that the contribution of visual inputs had changed after surgery, while at the same time, each patient used their static SVV as their reference point for orientation.     

Potential of an Interorgan Network Mediated by Toxic Advanced Glycation End-Products in a Rat Model

Excessive intake of glucose and fructose in beverages and foods containing high-fructose corn syrup (HFCS) plays a significant role in the progression of lifestyle-related diseases (LSRD). Glyceraldehyde-derived advanced glycation end-products (AGEs), which have been designated as toxic AGEs (TAGE), are involved in LSRD progression. Understanding of the mechanisms underlying the effects of TAGE on gene expression in the kidneys remains limited. In this study, DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were used to investigate whether HFCS-consuming Wister rats generated increased intracellular serum TAGE levels, as well as the potential role of TAGE in liver and kidney dysfunction. HFCS consumption resulted in significant accumulation of TAGE in the serum and liver of rats, and induced changes in gene expression in the kidneys without TAGE accumulation or upregulation of receptor for AGEs (RAGE) upregulation. Changes in specific gene expression profiles in the kidney were more correlated with TAGE levels in the liver tissue than in the serum. These findings suggest a direct or indirect interaction may be present between the liver and kidneys that does not involve serum TAGE or RAGE. The involvement of internal signal transduction factors such as exosomes or cytokines without IL-1β and TNF-α is suggested to contribute to the observed changes in kidney gene expression.     

Differential diagnosis of kidney transplant rejection and cyclosporin/tacrolimus nephropathy using urine cytology

Abstract: A total of 9000 urine samples from 69 kidney transplant recipients were studied for differential diagnoses of transplant rejection and cyclosporin/tacrolimus toxicity. New–Sternheimer and Papanicolaou staining were used to differentiate cells in urine. We also employed an immunocytochemical technique for further identification of exfoliated cells. With New–Sternheimer and Papanicolaou staining, the predominance of proximal tubular cells was useful to differentiate cyclosporin/tacrolimus toxicity from acute rejection in cases of increased serum creatinine level. During rejection episodes, an increased number of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase of CD2-, CD4- CD8-, CD25- and HLA-DR-positive cells with rejection. However, there was no relationship between Banff criteria rejection grade and the increase of mononuclear cells.     

Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin-angiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI2 in renovascular hypertension in vivo, employing mice lacking the PGI2 receptor (IP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.